Riboflavin (vitamin B2) serves as precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), essential molecules which act as cofactors for several oxidoreductases that are indispensable in living cells. Riboflavin synthase catalyzes the terminal step in riboflavin biosynthesis. In this complex dismutation reaction (under research for more than four decades) one lumazine molecule (6, 7-dimethyl-8-(1/-D-ribityl)-lumazine) serves as donor of a C4-carbon unit, which is transferred to a second lumazine molecule. This generates riboflavin and a pyrimidindione derivative, which can be recycled by the metabolic (one step) upwards standing lumazine synthase. In the past years it could be shown, that riboflavin synthases from yeast and bacteria exist as trimers in solution. Crystallographic studies (and modelling studies) suggest that riboflavin synthases can be regarded as asymmetric trimers, consequently only one reaction centre is competent to catalyze the reaction at a given time. In detail it was proposed, that trimeric riboflavin synthases execute extensive conformational changes, which result in a temporary pseudo-C2-symmetry between adjacent monomers. According to this model a C4-carbon unit from one substrate, bound at the C-terminal domain is transferred to the substrate bound at the N-terminal domain of the adjacent monomer. In this study it could be shown on the one hand that archaeal riboflavin synthases – contrary to the hitherto known trimeric riboflavin synthases - represent homo pentamers, and on the other hand that the riboflavin biosynthesis results in an rigid asymmetric cavity, generated by adjacent monomers of the pentamer. In the complex structure both substrate analogon molecules show an anti-parallel endo-like conformation, which is mainly guaranteed by a network of hydrogen bonds. The results demonstrate a different folding pattern to trimeric riboflavin synthases. Essentially the folding pattern corresponds to the three dimensional structure of the metabolic (one step in riboflavin biosynthesis) upwards standing lumazine synthase. This homology allows us to postulate a new hypothesis of the evolution and origin of this metabolic pathway. In addition (based on the topology of the complex structure), all the hypothetical reaction mechanisms can be discussed in a way that was previously not possible; in detail a reaction sequence, which represents an Diels-Alder-reaction. The geometry of the complex structure shows that this model is attractive. The model of the positioning of the pentacyclic reaction intermediate verifies the postulate of the first reported case in metabolism that an enzyme (pentameric and trimeric riboflavin synthase, with two different folds) catalyzes a reaction via two different diastereomeric reaction intermediates. The results, concerning the comparison of the cavities of lumazine and riboflavin synthases, and the (now) possible new evaluation of the different reaction models may be a guideline for the development of new inhibitors affecting lumazine and riboflavin synthases from pathogenic organisms. «

Riboflavin (vitamin B2) serves as precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), essential molecules which act as cofactors for several oxidoreductases that are indispensable in living cells. Riboflavin synthase catalyzes the terminal step in riboflavin biosynthesis. In this complex dismutation reaction (under research for more than four decades) one lumazine molecule (6, 7-dimethyl-8-(1/-D-ribityl)-lumazine) serves as donor of a C4-carbon unit, which is transfe... »